PROJECT SUMMARY: Overall The primary scientific focus of this Center is to understand the molecular underpinnings of EWS-ETS driven Ewing sarcoma and to investigate novel treatments and therapeutic mechanisms to improve outcomes for pediatric patients with this aggressive disease. Translation of molecular understanding of sarcoma pathophysiology into effective new drugs in the clinic is a complex, risky proposition that requires the coordinated efforts of a talented team of individuals with complementary skills. This group brings expertise in Ewing sarcoma biology and the EWS-ETS oncoproteins, epigenetics and transcription, structural biology, computational biology, chemical biology and drug development, mouse models, preclinical experimental therapeutics, and clinical trials development. A Center mechanism is essential to the success of this proposal. No one institution nor individual can bring mastery of the diversity of approaches, technologies, and scientific domains needed to achieve the goals of this proposal. We have elected to focus on understanding the fundamental inner workings of Ewing sarcoma from its transcriptional circuits, to the direct protein interactions with EWS-FLI1, to the direct and immediate effects of EWS-FLI1 degradation. Moreover, a strong emphasis of this proposal is on target identification and preclinical validation, critical steps in the process of bringing forward therapies with optimal chances for success in the clinic. The team that is assembled has all of the component pieces needed for success. Our Center includes outstanding basic cancer biologists, chemists, computational biologists, and translational researchers, and five pediatric oncologists. Thus, the proposed Center can catalyze basic discovery and clinical translation by leveraging basic and clinical research talent within the Center and our strong ties to outside academic and industrial partners.